ABSTRACT The goal of this proposal is to develop tumor necrosis factor ? (TNF?)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer?s disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-? as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNF? is a ?druggable? molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound shows potent TNF? inhibition in vitro. Our Phase 1 SBIR studies demonstrate that our small molecule TNF? inhibitor administered orally or peripherally significantly improved cognitive function in multiple AD mouse models. Our compound also modulated brain TNF? protein levels, microglial activation, and the progress of AD-associated neuropathology. No morbidity, mortality or any obvious side effects were observed despite long-term oral daily treatment regimen with our compound. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed SBIR phase 2 grant studies will de-risk further development of our compound by 1) finding a new synthetic method that is viable for commercial manufacturing and 2) performing key early safety toxicology studies in preparation for future FDA-required IND enabling studies.